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Text
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URL Address
<a href="http://doi.org/10.1158/1535-7163.mct-13-0132" target="_blank" rel="noreferrer noopener">http://doi.org/10.1158/1535-7163.mct-13-0132</a>
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Pages
2389-2399
Issue
11
Volume
12
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Title
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Paclitaxel-Hyaluronic NanoConjugates Prolong Overall Survival in a Preclinical Brain Metastases of Breast Cancer Model
Publisher
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Molecular Cancer Therapeutics
Date
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2013
2013-11
Subject
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stem-cells; in-vivo; Oncology; central-nervous-system; lipid rafts; antitumor-activity; multidrug-resistance; acid-paclitaxel; cd44 expression; p-glycoprotein; targeted drug-delivery
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Mittapalli R K; Liu X L; Adkins C E; Nounou M I; Bohn K A; Terrell T B; Qhattal H S; Geldenhuys W J; Palmieri D; Steeg P S; Smith Q R; Lockman P R
Description
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Brain (central nervous system; CNS) metastases pose a life-threatening problem for women with advanced metastatic breast cancer. It has recently been shown that the vasculature within preclinical brain metastasis model markedly restricts paclitaxel delivery in approximately 90% of CNS lesions. Therefore to improve efficacy, we have developed an ultra-small hyaluronic acid (HA) paclitaxel nanoconjugate (similar to 5 kDa) that can passively diffuse across the leaky blood-tumor barrier and then be taken up into cancer cells (MDA-MB-231Br) via CD44 receptor-mediated endocytocis. Using CD44 receptor-mediated endocytosis as an uptake mechanism, HA-paclitaxel was able to bypass p-glycoprotein-mediated efflux on the surface of the cancer cells. In vitro cytoxicity of the conjugate and free paclitaxel were similar in that they (i) both caused cell-cycle arrest in the G(2)-M phase, (ii) showed similar degrees of apoptosis induction (cleaved caspase), and (iii) had similar IC50 values when compared with paclitaxel in MTT assay. A preclinical model of brain metastases of breast cancer using intracardiac injections of Luc-2 transfected MDA-MB-231Br cells was used to evaluate in vivo efficacy of the nanoconjugate. The animals administered with HA-paclitaxel nanoconjugate had significantly longer overall survival compared with the control and the paclitaxel-treated group (P < 0.05). This study suggests that the small molecular weight HA-paclitaxel nanoconjugates can improve standard chemotherapeutic drug efficacy in a preclinical model of brain metastases of breast cancer. (C) 2013 AACR.
Identifier
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<a href="http://doi.org/10.1158/1535-7163.mct-13-0132" target="_blank" rel="noreferrer noopener">10.1158/1535-7163.mct-13-0132</a>
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Journal Article or Conference Abstract Publication
2013
acid-paclitaxel
Adkins C E
antitumor-activity
Bohn K A
cd44 expression
central-nervous-system
Geldenhuys W J
in-vivo
Journal Article or Conference Abstract Publication
lipid rafts
Liu X L
Lockman P R
Mittapalli R K
Molecular cancer therapeutics
multidrug-resistance
Nounou M I
oncology
p-glycoprotein
Palmieri D
Qhattal H S
Smith Q R
Steeg P S
stem-cells
targeted drug-delivery
Terrell T B